Retinoids, steroid and thyroid hormones and possibly other molecules produce their biological effects by binding to proteins of the steroid receptor superfamily. These receptors interact with specific DNA sequences and modulate gene expression (for reviews see J M Berg, Cell 57:1065-1068 (1989); R M Evans, Science 240:899-895 (1988); M Beato, Cell 56:335-344 (1989)). Sequence analysis and functional studies of these receptors revealed two important regions which exhibit a high degree of amino acid residue conservation. The highest level of similarity among the receptors is found in a region which contains nine cysteine residues that bind zinc atoms to form two "zinc fingers," which interact with the cognate steroid response elements of DNA (J Miller, et al., EMBO J 4:1609-1614 (1985); R M Evans, Cell 52:1-3 (1988)). The second region, which is less conserved, is the ligand-binding domain, responsible for the interaction with the hormone (J. Carlstedt-Duke, et al., Proc Natl Acad Sci USA 79:4260-4264 (1982). J. Carlstedt-Duke, et al., Proc Natl Acad Sci USA 84:4437-4440 (1987)). Recent studies have attributed additional functions to other domains of these receptors, such as protein-protein interaction that participates in transcriptional regulation (R Scule, et al., Cell 62:1217-1226 (1990); H F Yang, Cell 62:1205-1215 (1990); J M Holloway et al., Proc Natl Acad Sci USA 87:8160-8164 (1990)). The amino acid conservation in the DNA binding domain has led to the identification of new members of the steroid receptor superfamily.
For example, hER1 and hER2 have been cloned by low stringency hybridization of cDNA libraries with a DNA probe coding for the DNA binding domain of the estrogen receptor (Giguere, et al., Nature 331:91-94 (1988)). Similar approaches have led to the discovery of the retinoic acid receptors and the peroxisome proliferator activator receptor (PPAR) (I Issemann, et al., Nature 347:645-650 (1990); D J Mangelsdorf, et al., Nature 345:224-229 (1990)). Recently, three novel members of the Xenopus nuclear hormone receptor superfamily have been disclosed (C Dreyer, Cell 68:879-987 (1992)). In addition, U.S. Pat. No. 4,981,784 to Evans, et al. discloses the identification of a retinoic acid receptor and the use of chimeric constructs to produce hybrid receptors for the identification of novel ligands. The above references, however, neither disclose nor suggest the instant invention.
TOFA (5-(tetradecyloxy)-2-furan-carboxylic acid) has been reported to inhibit fatty acid synthesis by inhibiting acetyl-CoA carboxylase, the rate limiting step in de novo fatty acid synthesis, in vivo ##STR1## at high doses, i.e. 0.15% of diet . (See, e.g. Arbeeny, "Inhibition of fatty acid synthesis decreases renal low density lipoprotein secretion in the hamster," J. Lipid Res. 33: 843-851, (1992); Ribeneau-Gyon and Gilles, FEBS Lett. 62: 309-312, (1976); Halvorson and McCune, "Inhibition of fatty acid synthesis in isolated adipocytes by 5-tetradecyloxy)-2-furoric acid," Lipids 19(11): 851-856, (1984); Otto et al., "Reciprocal effects of 5-(tetradecyloxy)-2-fuoric acid on fatty acid oxidation," Arch. Biochem. Biophys. 242(1):23-31, (1985); Parker et al., "5-(tetradecyloxy)-2-furancarboxylic acid and related hypolipidemic fatty acid-like alkyloxyarylcarboxylic acids," J. Med. Chem. 20:781-791, (1977)). The present invention comprises in one embodiment the use of low-dose TOFA to potentiate the activity of ligands of G-coupled receptors and to potentiate the activity of endogenously produced hormones or neurotransmitters.
Powell et al., ("Dopamine activation of an orphan of the steroid receptor family" Science 252: 1546-48, (1991), and "Dopaminergic and ligand independent activation of steroid hormone receptors" Science 254: 1636-39, (1991)) have reported that dopamine activates transcription, mediated by steroid hormone receptors, by a ligand-independent mechanism. However, unlike dopamine, TOFA and activators of NER do not themselves have dopaminergic activity at the dosage level used.
Dopamine receptors are membrane proteins that have seven transmembrane domains and mediate transmembrane signaling via the heterotrimeric G proteins. The receptors are predominantly localized in the central nervous system, but peripheral organs such as the kidney, lower esophagus and cardiac and mesenteric arteries also respond to dopamine through specific binding sites. (Strange, "Dopamine receptors: structure and function," Prog Brain Res. 99:167-79, (1993); Strange, "New insights into dopamine receptors in the central nervous system," Neurochem. Int. 22(3):223-236, (1993).) Molecular cloning revealed that this receptor family consists of five genes, D1-D5, that modulate the activity of adenyl cyclase. The D1 and D5 dopamine receptors stimulate adenylyl cyclase activity, while the D2, D3 and D4 receptors inhibit this enzyme. (Seeman and Van-Tol, "Dopamine receptor pharmnacology," Curr. Opin. Neurol. Neurosurg. 6(4):602-609, (1993); Kebabian, "Multiple dopamine receptors and their implications in medicine," Curr. Opin. Neurol. Neurosurg. 5(4): 514-518, (1992); Kebabian, "Brain dopamine receptors: 20 years of progress," Neurochem. Res. 18(1):101-104, (1993); Sibley, et al., "Molecular neurobiology of dopaminergic receptors," Int. Rev. Neurobiol. 35:391-415, (1993).)
Dopaminergic agents and their antagonists serve to treat movement disorders, other neuropsychiatric disorders, nausea, and certain hormonal disorders.
Dopamine D.sub.1 receptors are coupled to adenyl cyclase. Known Dopamine D.sub.1 antagonists include SCH23390 (8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hemimaleate): ##STR2## Dopamine D1 antagonists have demonstrated a role in the treatment of Alzheimer's disease. In the radial-arm maze test, an assay used for testing memory enhancing agents, medial cholinergic pathway lesions produce evidence of memory loss and chronic treatment with SCH23390 reversed the lesion-induced impaired performance. (McGurk et al. "Dopaminergic drugs reverse the impairment of radial-arm maze performance caused by lesions involving the cholinergic medial pathway," Neuroscience. 50(1):129-135, (1992)).
Dopamine D1 receptor antagonists are also useful in the treatment of movement disorders such as Gilles de la Tourette syndrome, dystonia, and tardive dyskinesia. Dopamine D1 receptor antagonists are also useful in treating psychoses, most particularly schizophrenia.
Gilles de la Tourette syndrome, or hereditary multiple tic disorder, begins in childhood with simple tics but progresses to multiple, complex movements including respiratory and vocal tics. In 50% of patients, coprolalia, involuntary scatologic utterances, occurs. The tics and coprolalia may be severe enough to be physically and socially disabling. Gilles de la Tourette syndrome is generally treated with haloperidol, 0.5 to 40 mg/day. The dosage of haloperidol is limited by side effects such as dysphonia, parkinsonism and akathisia. Clonidine, 0.1 to 0.6 mg/day may also be effective in some patients, but is limited by the side effect of hypotension. The present invention, by potentiating the dopamine D1 receptor antagonists, permits the treatment of Gilles de la Tourette syndrome with a decreased administration of dopamine D1 receptor antagonists.
Dystonia is characterized by sustained abnormal postures and disruptions of ongoing movement resulting from alterations in muscle tone. Dystonia is generally treated with high dose anticholinergics such as trihexyphenidyl 6 to 30 mg/day, benztropine 3 to 14 mg/day, and reserpine, a dopamine depleting drug, 0.1 to 0.6 mg/day.
Tardive dyskinesia is characterized by choreiform movements of the buccal-lingual-fascial muscles, less commonly the extremities. Rarely, focal or even generalized dystonia may be seen. Tardive dyskinesia may be caused by high doses of phenothiazines given over a long time, a common practice in young schizophrenics. Older patients, particularly women and those with brain injury, have a higher incidence of tardive dyskinesia. The problem does not disappear when the drug is discontinued and resists standard treatments for movement disorders. Anticholinergics can exascerbate tardive dyskinesia. The incidence has increased with the common and prolonged use of phenothiazines. By potentiation the effect of dopamine D1 receptor antagonists administered, NER receptor activators such as TOFA, are useful in the prevention of tardive dyskinesia.
Known dopamine D1 receptor agonists include SKF 38390 (1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine): ##STR3##
Dopamine D.sub.1 receptor agonists are useful in treating Parkinson's Disease.
Haloperidol is a preferential blocker of dopamine D2 receptors. Other Dopamine D.sub.2 receptor modulators include dihydroergocryptine and bromocryptine. ##STR4##
The muscarinic receptors naturally bind acetylcholine. ##STR5## The plant alkaloid muscarine also activates the muscarinic cholinergic receptors. ##STR6##
Muscarinic receptors occur at post ganglionic parasympathetic terminals involved in gastrointestinal and ureteral peristalsis, the promotion of glandular secretion, pupillary constriction, peripheral vasodilation and reduction in heart rate. The muscarinic receptor is also a G-protein coupled receptor, and its stimulation causes an increase in cGMP. Pilocarpine is a known muscarinic agonist. ##STR7## Others include carbachol, metacholine, betanechol, arecoline, and oxotremorine. ##STR8## Muscarinic agonists are useful for the treatment of ocular hypertension, particularly in glaucoma, and to stimulate the gastrointestinal tract and urinary bladder to relieve post operative atony.
NGF, nerve growth factor, is required for the development of sympathetic and sensory neurons and for neuronal viability in mature brain cells. NGF treatment induces the expression of the immediate early response gene--the orphan steroid hormone receptor Nur77. (Davis et al., "Transcriptional activation by Nur77, a growth factor inducible member of the steroid hormone receptor superfamily. Mol Endocrinol. 5(6): 854-859, 1991; Hazel et al., "Nur77 is differentially modified in PC12 cells upon membrane depolarization and growth factor treatment," Mol Cell Biol 11(6):3293-3246, 1991; Milbrandt, "Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene," Neuron 1(3):183-188, 1993). Due to its role in neuronal maintenance and its ability to stimulate nerve growth, NGF is potentially important for the treatment of Alzheimer's disease. (Olson, "Reparative strategies in brain-treatment strategies based on trophic factors and cell transfer techniques," Acta Neurochirurgica 58:3-7, 1993). The potential benefit of NGF in Alzheimer's disease is also suggested by the recent demonstration of memory improvement following intracranial infusion of NGF in an Alzheimer's patient. Thus, NGF appears to be able to counteract the cholinergic deficits of Alzheimer's disease. (Seiger et al. "Intercranial infusion of purified nerve growth factor to an alzheimer patient," Behavioral Brain Research 57:255-261, 1993).